NM_000321.3:c.607+1G>A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000321.3(RB1):c.607+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000321.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RB1 | NM_000321.3 | c.607+1G>A | splice_donor_variant, intron_variant | Intron 6 of 26 | ENST00000267163.6 | NP_000312.2 | ||
RB1 | NM_001407165.1 | c.607+1G>A | splice_donor_variant, intron_variant | Intron 6 of 26 | NP_001394094.1 | |||
RB1 | NM_001407166.1 | c.607+1G>A | splice_donor_variant, intron_variant | Intron 6 of 16 | NP_001394095.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RB1 | ENST00000267163.6 | c.607+1G>A | splice_donor_variant, intron_variant | Intron 6 of 26 | 1 | NM_000321.3 | ENSP00000267163.4 | |||
RB1 | ENST00000467505.5 | n.138-10993G>A | intron_variant | Intron 1 of 2 | 1 | ENSP00000434702.1 | ||||
RB1 | ENST00000650461.1 | c.607+1G>A | splice_donor_variant, intron_variant | Intron 6 of 26 | ENSP00000497193.1 | |||||
RB1 | ENST00000525036.1 | n.769+1G>A | splice_donor_variant, intron_variant | Intron 6 of 6 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Retinoblastoma Pathogenic:3
This sequence change affects a donor splice site in intron 6 of the RB1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with retinoblastoma (PMID: 7795591, 34277001). In at least one individual the variant was observed to be de novo. This variant is also known as intron 6+1G>A. ClinVar contains an entry for this variant (Variation ID: 419970). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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Case and Pedigree Information: BILATERAL CASES:9, UNILATERAL CASES:0, TOTAL CASES:9, PEDIGREES:9. ACMG Codes Applied:PVS1, PM2, PS4SUP -
not provided Pathogenic:2
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as g.45867G>A; This variant is associated with the following publications: (PMID: 25525159, 7795591, 14722923, 8776589, 12541220, 16343894, 17096365, 33493472, 34277001) -
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Hereditary cancer-predisposing syndrome Pathogenic:1
The c.607+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the RB1 gene. This pathogenic mutation has been reported in numerous individuals with bilateral retinoblastoma (Blanquet V et al. Hum. Mol. Genet. 1995 Mar;4:383-8; Houdayer C et al. Hum. Mutat. 2004 Feb;23:193-202; Nichols KE et al. Hum. Mutat. 2005 Jun;25:566-74; Brichard B et al. Eur. J. Cancer 2006 Jan;42:65-72). Of note, this alteration is also referred to as 745+1G>A and g.45867G>A in the literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Lynch syndrome 4 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at